AKT3 Gene Transfer Promotes Anabolic Reprogramming and Photoreceptor Neuroprotection in a Pre-clinical Model of Retinitis Pigmentosa

Abstract

Mutations within over 250 known genes are associated with inherited retinal degeneration. Clinical success following genereplacement therapy for congenital blindness due to RPE65 mutations establishes a platform for the development of downstream treatments targeting other forms of inherited ocular disease. Unfortunately, several challenges relevant to complex disease pathology and limitations of current gene-transfer technologies impede the development of related strategies for each specific form of inherited retinal degeneration. Here, we describe a gene-augmentation strategy that delays retinal degeneration by stimulating features of anabolic metabolism necessary for survival and structural maintenance of photoreceptors. We targeted two critical points of regulation in the canonical insulin/AKT/mammalian target of rapamycin (mTOR) pathway with AAV-mediated gene augmentation in a mouse model of retinitis pigmentosa. AAV vectors expressing the serine/threonine kinase, AKT3, promote dramatic preservation of photoreceptor numbers, structure, and partial visual function. This protective effect was associated with successful reprogramming of photoreceptor metabolism toward pathways associated with cell growth and survival. Collectively, these findings underscore the importance of AKT activity and downstream pathways associated with anabolic metabolism in photoreceptor survival and maintenance.

Endoplasmic reticulum stress: New insights into the pathogenesis and treatment of retinal degenerative diseases

“…To regulate translation, mTOR directly phosphorylates regulators of protein synthesis, including 4E-BPs (Gingras et al, 1999;Gingras et al, 1998) and S6 kinase (Garami et al, 2003). We demonstrated that the pAKT axis is downregulated in degenerating retinas of mouse models of IRD (Starr et al, 2018), and others validated the AKT gene transfer approach to rescue degenerating photoreceptors (McDougald et al, 2019).…”

The variation in promoter sequences of the Akt3 gene between cow and buffalo revealed different responses against mastitis

“…Thus, the promoter activity is sustained by two core function promoter regions. This could play a key role in the inflammatory response and variation for susceptibility in buffalo and cows for mastitis or any other inflammatory disease [ 26 ]. Also, Jin et al [ 27 ] mentioned that the differences in promoter region length could significantly affect the numbers of cell metabolic pathways that could make the differences in responses to the infections.…”

Photoreceptor metabolic reprogramming: current understanding and therapeutic implications

“…Constitutive activation of mTORC1 by genetically deleting inhibitors Pten and tuberous sclerosis complex protein 1 ( Tsc1 ) enhances survival and function of cones in retinal degeneration models 45 . Similarly, augmentation of AKT activity protects rod and cone structural and functional integrity in RP models 97 . Neuroprotection via mTOR and AKT activation is attributed to improved glucose uptake, retention, and utilization by PRs 45 .…”